Neuropathic pain is thought to occur because of a sensitization in the peripheral and central nervous systems after an initial injury to the peripheral system (see N. Attal, 2000, Clin. J. Pain 16(3 Suppl):S118–30). Direct injury to the peripheral nerves as well as many systemic diseases including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and various autoimmune diseases, can induce this disorder. Such pain is also associated with conditions of the bladder, including interstitial cystitis. Neuropathic pain is typically experienced as burning, shooting, and unrelenting in its intensity, and can sometimes be more debilitating that the initial injury or the disease process which induced it. Unfortunately, the few remedies that have been reported to alleviate this condition are effective in only a small percentage of patients.
Interstitial cystitis (IC) is characterized by bladder pain, irritative voiding symptoms, and sterile urine (see R. Doggweiler-Wiygul et al., 2000, Curr. Rev. Pain 4(2):137–41). In IC, the bladder wall shows inflammatory infiltration with mucosal ulceration and scarring that causes smooth muscle contraction, diminished urinary capacity, hematuria, and frequent, painful urination. Although the pathogenesis of IC is uncertain, it seems likely that a dysfunctional epithelium results in the transepithelial migration of solutes, such as potassium, which depolarizes sensory nerves, and produces the symptoms (C. L. Parsons et al., 1991, J. Urol. 145:732; C. L. Parsons et al., 1994, J. Urol. 73:504; G. Hohlbrugger, 1999, Br. J. Urol. 83(suppl. 2):22; C. L. Parsons et al., 1998, J. Urol. 159:1862). Previous reports have shown that IC patients have defects in the glycosaminoglycan (GAG) layers of the uroepithelium (C. L. Parsons et al., 1991, J. Urol. 145:732; C. L. Parsons et al., 1994, J. Urol. 73:504; G. Hohlbrugger, 1999, Br. J. Urol. 83(suppl. 2):22). Thus, therapies that restore the mucosal lining or surface GAG layer, e.g., administration of heparine, hyaluronic acid, or pentosanpolysulfate, can reduce the leakage of irritant and result in palliation of IC symptoms (see, e.g., C. L. Parsons et al., 1994, Br. J. Urol. 73:504; J. I. Bade et al., 1997, Br. J. Urol. 79:168; J. C. Nickel et al., 1998, J. Urol. 160:612).
Capsaicin is a homovanillic acid derivative (8-methyl-N-vanillyl-6-nonenamid). It is the active component of the red pepper of the genus Capsicum, and has been used in humans for topical treatment of cluster headache, herpes zoster, and vasomotor rhinitis (see P. Holzer, 1994, Pharmacol. Rev. 43:143; Sicuteri et al., 1988, Med. Sci. Res. 16:1079; Watson et al., 1988, Pain 33:333; Marabini et al., 1988, Regul. Pept. 22:1). In vitro capsaicin modulates cellular growth, collagenase synthesis, and prostaglandin secretion from rheumatoid arthritis synoviocytes (see Matucci-Cerinic et al., 1990, Ann. Rheum. Dis. 49:598). Capsaicin has also been shown to be immunomodulatory as indicated by its ability to modulate lymphocyte proliferation, antibody production, and neutrophil chemotaxis (see Nilsson et al., 1988, J. Immunopharmac. 10:747; Nilsson et al., 1991, J. Immunopharmac. 13:21; and Eglezos et al., 1990, J. Neuroimmunol. 26:131). These effects play an important role in the use of capsaicin for treatment of arthritis. In addition, capsaicin induces mitochondrial swelling, inhibits NADH oxidase, induces apoptosis of transformed cells, stimulates adenylate cyclase, activates protein kinase C, inhibits superoxide anion generation and alters the redox state of the cell.
The various effects of capsaicin are mediated through a specific cellular receptor referred to as a vanilloid receptor. This receptor is shared by resiniferatoxin, an alkaloid derived from plants of the genus Euphorbia. Resiniferatoxin is a structural homologue of capsaicin, and has been shown to mimic many of the actions of capsaicin. Resiniferatoxin is also structurally similar to phorbol esters (phorbol myristate acetate), which interact with distinct binding sites and activate protein kinase C (see Szallasi, et al., 1989, Neurosci. 30:515; and Szallasi and Blumberg, 1989, Neurosci. 30:515). Unlike resiniferatoxin, capsaicin has no homology to phorbol myristate acetate. However, capsaicin can activate protein kinase C, suggesting that such activation is not due entirely to the phorbol ester-like moiety on resiniferatoxin.
Capsaicin has been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers, or C fibers, which mediate pain. From studies in animals, capsaicin appears to trigger C fiber membrane depolarization by opening cation selective channels for calcium and sodium. Although detailed mechanisms of action are not yet known, capsaicin mediated effects include: (I) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive unmyelinated C fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of C fibers without affecting the number of myelinated fibers.
Because of the ability of capsaicin to desensitize nociceptors in peripheral tissues, its potential analgesic effects have been assessed in various clinical trials. U.S. Pat. No. 5,431,914, issued Jul. 11, 1995, suggests that a topical preparation containing a concentration of capsaicin of about 0.01% to about 0.1% could be used to treat internal organ pathologies. U.S. Pat. No. 5,665,378, issued Sep. 9, 1997, discusses a transdermal therapeutic formulation comprising capsaicin, a non-steroidal anti-inflammatant, and pamadorm (a diuretic agent) where the composition is said to contain from about 0.001–5% by weight capsaicin and to be useful in treating the pain and discomfort associated with menstrual cramps, bloating, and/or muscular pain such as muscular back pain. Several studies have assessed intravesical capsaicin as a treatment for urge incontinence in patients with spinal detrusor hyperreflexia or bladder hypersensitivity disorders (see F. Cruz, 1998, Int. Urogynecol. J. Pelvic Floor Dysfunct. 9:214–220).
However, since capsaicin application itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated, patient compliance has been poor and the drop out rates during clinical trials have exceeded fifty percent. The spontaneous burning pain and heat hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of capsaicin application (primary hyperalgesia). Mechanical hyperalgesia evident in areas surrounding the site of topical application appears to originate from central sensitization of dorsal horn neurons involved in pain transmission (secondary hyperalgesia). Because of these side effects, the maximal capsaicin concentration used in previous human studies has usually been limited to 0.075%.
Dystonias are neurological movement disorders characterized by involuntary muscle contractions that force certain parts of the body into abnormal, sometime painful, movements or postures (see S. B. Bressman, 2000, Clin. Neuropharmacol. 23(5):239–51). Dystonia disorders cause uncontrolled movement and prolonged muscle contraction, which can result in spasms, twisting body motions, tremor, or abnormal posture. These movements may involve the entire body, or only an isolated area, such as the arms and legs, trunk, neck, eyelids, face, bladder sphincter, or vocal cords. Dystonias result from environmental or disease-related damage to the basal ganglia, birth injury, (particularly due to lack of oxygen), certain infections, reactions to certain drugs, heavy-metal or carbon monoxide poisoning, trauma, or stroke can cause dystonic symptoms. Dystonias can also be symptoms of other diseases, some of which may be hereditary.
Urinary detrusor-sphincter dyssynergia (UDSD; also called detrusor-external sphincter dyssynergia and urethral dyssynergia) is a specific type of neurological movement disorder (see H. Madersbacher, 1990, Paraplegia 28(4):217–29; J. T. Andersen et al., 1976, J. Urol. 116(4):493–5). UDSD is characterized by involuntary urinary sphincter spasms occurring simultaneously with bladder contractions. The lack of coordination between detrusor contraction and urethral relaxation causes urinary obstruction (i.e., partial or complete block of urination). As a result of UDSD, the bladder cannot empty completely. This creates a buildup of urinary pressure, and can lead to severe urinary tract damage and life-threatening consequences. UDSD results from lesions of the corticospinal tract, which are caused by spinal chord injury, multiple sclerosis, or related conditions.
Another neurological movement disorder is hyperactive (also called contracted; spastic) neurogenic bladder (see M. H. Beers and R. Berkow (eds), 1999, The Merck Manual of Diagnosis and Therapy, Section 17:Genitourinary Disorders, Chapter 216: Myoneurogenic Disorders). In hyperactive bladder, the bladder contracts more frequently than normal, due to instability and inappropriate contraction of detrusor muscles (see, e.g., C. F. Jabs et al., 2001, Int. Urogynecol. J. Pelvic Floor Dysfunct. 12(1):58–68; S. K. Swami and P. Abrams, 1996, Urol. Clin. North Am. 23(3):417–25). Hyperactive bladders can empty spontaneously and result in urinary incontinence (urge incontinence). In addition, the uncoordinated contraction between the bladder and bladder outlet (vesical neck or external urinary sphincter) can result in vesicoureteral reflux with concomitant renal damage. Hyperactive bladder is usually due to brain or suprasacral spinal cord damage. The most common cause is spinal cord injury from transverse myelitis or traumatic cord transection. Hyperactive bladder can also be caused by conditions such as anxiety, aging, infections (e.g., syphilis), diabetes mellitus, brain and spinal cord tumors, stroke, ruptured intervertebral disk, and demyelinating and degenerative diseases (e.g., multiple sclerosis and amyotrophic lateral sclerosis).
Botulinum toxins are zinc endopeptidases produced by the anaerobic bacterium Clostridium botulinum. Previously known as a cause of a serious and often fatal paralysis acquired through ingestion of contaminated food, botulinum neurotoxins are presently used in both therapeutic and cosmetic applications (see N. Mahant et al., 2000, J. Clin. Neurosci. 7(5):389–94; A. Carruthers and J. Carruthers, 2001, Semin. Cutan. Med. Surg. 20(2):71–84). In particular, these toxins are used in the treatment of conditions involving involuntary muscle spasms, frown lines, and facial wrinkles.
There are seven known serotypes of botulinum toxins (designated A–G). The serotypes differ in their cellular targets, potency, and duration of action, but all exert their paralytic effect by inhibiting acetylcholine release at the neuromuscular junction (see M. F. Brin, 1997, Muscle Nerve 20(suppl 6):S146–S168). Each serotype acts by cleaving one or more proteins involved in vesicle transport and membrane fusion. For example, botulinum toxin A is internalized by endocytosis at the axon terminal, where it is fully activated by disulfide reduction reactions, and it targets SNAP-25 (see M. F. Brin, 1997, Muscle Nerve 20(suppl 6):S146–S168). The extent of botulinum toxin-mediated paralysis depends on the dose, volume, and serotype employed. Botulinum toxin A causes reversible denervation atrophy that is typically terminated by axon sprouting within 2–6 months (see M. F. Brin, 1997, Muscle Nerve 20(suppl 6):S146–S168).
A major drawback of current botulinum toxin therapies is the development of antitoxin antibodies in patients. Antitoxin antibodies result in resistance to botulinum toxin, and the reduction or elimination of its therapeutic effect. It has been estimated that the prevalence of neutralizing antibodies among patients receiving chronic treatment at the higher doses for torticollis or spasticity is probably at least 3% (see M. F. Brin, 1997, Muscle Nerve 20(suppl 6):S146–S168). Patients with botulinum toxin A resistance may benefit from injections with other serotypes, including botulinum toxin B, C, and F. However, differences in the duration of the effects of the other serotypes can be significant, and cause dramatic reductions in treatment efficacy (see M. F. Brin, 1997, Muscle Nerve 20(suppl 6):S146–S168).
Liposomes are self-assembling structures comprising concentric amphipathic lipid (e.g., phospholipid) bilayers separated by aqueous compartments (see, e.g., K. Reimer et al., 1997, Dermatology 195(suppl. 2):93; M. Schafer-Korting et al., 1989, Dermatology 21:1271). In liposomes, the amphipathic lipid molecules comprise a polar headgroup region covalently linked to one or two non-polar acyl chains. The energetically unfavorable contact between the hydrophobic acyl chains and the aqueous solution surrounding the lipid molecules causes the polar headgroups and acyl chains to rearrange. The polar headgroups become oriented toward the aqueous solution, while the acyl chains orient towards the interior part of the bilayer. The lipid bilayer structure thereby comprises two opposing monolayers, wherein the acyl chains are shielded from contact with the surrounding medium.
Liposomes are excellent vehicles for drug delivery and gene therapy (K. Reimer et al., 1997, Dermatology 195(suppl. 2):93; T. Tsuruta et al., 1997, J. Urol. 157:1652; F. Szoka, 2000, Mol. Therapy 1:S2; G. Gregoriadis, 1976, New Eng. J. Med. 295:704). Previous studies have demonstrated that submucosal injection of liposomal doxorubicin into bladder wall provides an effective and safe treatment for bladder cancer with pelvic lymph node metastasis (I. Tsuruta et al., 1997, J. Urol. 157:1652). In a liposome-drug delivery system, an active ingredient, such as a drug, is encapsulated or entrapped in the liposome and then administered to the patient to be treated. Alternatively, if the active ingredient is lipophilic, it may be associated with the lipid bilayer. Active ingredients encapsulated by liposomes reduce toxicity, increase efficacy, or both. Notably, liposomes are thought to interact with cells by stable absorption, endocytosis, lipid transfer, and fusion (R. B. Egerdie et al., 1989, J. Urol. 142:390). In this way, liposomes comprise molecular films, which fuse with cells and provide optimal conditions for wound healing (K. Reimer et al., 1997, Dermatology 195(suppl. 2):93; M. Schafer-Korting et al., 1989, J. Am. Acad. Dermatol. 21:1271). Generally, liposomes have low antigenicity and can be used to encapsulate and deliver components that cause undesirable immune responses in patients (see A. Natsume et al., 2000, Jpn. J. Cancer Res. 91:363–367).